title: Enhancement of hepatitis C viral RNA abundance by precursor miR-122 molecules.
abstract: The hepatitis C viral RNA genome forms a complex with liver-specific microRNA (miR-122) at the extreme 5' end of the viral RNA. This complex is essential to stabilize the viral RNA in infected cultured cells and in the liver of humans. The abundances of primary and precursor forms of miR-122, but not the abundance of mature miR-122, are regulated in a circadian rhythm in the liver of animals, suggesting a possible independent function of precursor molecules of miR-122 in regulating viral gene expression. Modified precursor molecules of miR-122 were synthesized that were refractory to cleavage by Dicer. These molecules were found to enhance the abundance of HCV RNA. Furthermore, they diminished the expression of mRNAs that contained binding sites for miR-122 in their 3' noncoding regions. By use of duplex and precursor miR-122 mimetic molecules that carried mutations in the passenger strand of miR-122, the effects on viral and reporter gene expression could be pinpointed to the action of precursor miR-122 molecules. Targeting the circadian expression of precursor miR-122 by specific compounds likely provides novel therapeutic strategies.
authors.forename: Erica Machlin
authors.initials: EM
authors.lastname: Cox
authors.forename: Selena M
authors.initials: SM
authors.lastname: Sagan
authors.forename: Stefanie A W
authors.initials: SA
authors.lastname: Mortimer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doudna
authors.forename: Peter
authors.initials: P
authors.lastname: Sarnow
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001483:Base Sequence; D002940:Circadian Rhythm; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D055029:Inverted Repeat Sequences; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012322:RNA Precursors; D012367:RNA, Viral
keywords: Argonaute 2; Dicer; hepatitis C virus; microRNAs